Richard Rabkin

TESTOSTERONE THERAPY FOR HUMAN IMMUNODEFICIENCY VIRUS-POSITIVE MEN WITH AND WITHOUT HYPOGONADISM

This study was designed to evaluate the safety and effectiveness of testosterone therapy for clinical symptoms of hypogonadism (low libido, low mood, low energy, loss of appetite/weight) in human immunodeficiency virus-positive men with CD4 cell counts less than 400 cells/mm3 and deficient or low normal serum testosterone levels. The trial consisted of 8 weeks of open treatment with 400 mg of intramuscular testosterone cypionate biweekly. Responders were maintained at this dosage for another 4 weeks and then were randomized in a double-blind, placebo-controlled, 6-week discontinuation trial. Of the 112 men who completed at least 8 weeks of treatment, 102 (91%) were rated as responders on a global assessment of sexual desire/function. Of the 34 study completers with major depressive disorder and/or dysthymia, 79% reported significant improvement in mood at week 8. Average weight change was a gain of 3.7 pounds, with 45% gaining more than 5 pounds. Eighty-four men entered and 77 completed the double-blind phase; of these, 78% of completers randomized to testosterone and 13% randomized to placebo maintained their response. No significant medical or immunologic adverse effects were identified. Testosterone therapy was well tolerated and effective in ameliorating symptoms of clinical hypogonadism, and equally so for men with and without testosterone deficiency. For patients with major depression and/or dysthymia, improvement was equal to that achieved with standard antidepressants.

Testosterone versus fluoxetine for depression and fatigue in HIV/AIDS: a placebo-controlled trial.

Background: While testosterones ameliorative effects on depressive disorders and fatigue in HIV-positive patients have been suggested in the literature, no placebo-controlled trial selecting for depressive disorders and including a standard antidepressant has been conducted. Accordingly, this double-blind trial was designed to determine whether testosterone, as well as fluoxetine, is superior to placebo for depression, fatigue, or both. Method: One hundred twenty-three men with HIV/AIDS with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition depressive disorder entered the 8-week trial and were randomized to testosterone (up to 400 mg IM testosterone cypionate biweekly), fluoxetine (up to 60 mg/d), or double placebo. Outcome variables were the Clinical Global Impressions Scale for mood and for fatigue, the Hamilton Rating Scale for Depression, and the Chalder Fatigue Scale. Results: Ninety men completed the trial. In intention-to-treat analyses, mood response rates were 54%, 47%, and 44% for fluoxetine, testosterone, and placebo, respectively. Among completers, mood response rates were 70%, 57%, and 53%, respectively; in neither analysis were differences between treatments statistically significant. In contrast, testosterone was superior to fluoxetine and placebo for completers regarding fatigue. In intention-to-treat analysis, response rates were 39%, 56%, and 42% for fluoxetine, testosterone, and placebo, respectively, and for study completers, 41%, 63%, and 52%, respectively, (P < 0.05), Conclusion: While over 50% of patients treated with testosterone reported improved mood, this rate was not statistically superior to placebo. Thus, our findings do not support prescription of testosterone as a first-line treatment for depressive disorders in HIV-positive men. However, if validated in additional studies, testosterone may be a useful option for medically ill men experiencing significant fatigue as well as depression.

Modafinil treatment of fatigue in patients with ALS: A placebo-controlled study

Our objective was to determine whether modafinil alleviates fatigue in patients with amyotrophic lateral sclerosis (ALS). A placebo controlled trial with a 3:1 modafinil:placebo randomization in doses up to 300 mg/day for 4 weeks was followed by 8 weeks of open maintenance treatment. The primary endpoint was the Clinical Global Impressions‐Improvement Scale. Secondary endpoints were the Fatigue Severity Scale, Epworth Sleepiness Scale, Beck Depression Inventory, Role Function Scale, and visual analog scales. Analysis of covariance was used to assess change at Week 4. Thirty‐two patients were randomized; 29 completed the 4‐week trial. In intention to treat (ITT) analysis, the response was 76% for modafinil versus 14% for placebo. In a completer analysis, the modafinil response rate was 86%, and the placebo response rate remained 14%. The number needed to treat was 1.6 (ITT). No medically serious adverse events were reported. Modafinil may be a promising intervention for fatigue in ALS patients. Replication in a larger study is needed. Muscle Nerve 39: 297–303, 2009

Dextroamphetamine as a treatment for depression and low energy in AIDS patients: a pilot study.

This report documents findings from an open trial of dextroamphetamine in the treatment of depression and low energy in AIDS patients. Dextroamphetamine offers the potential for rapid onset of effect and activation properties, both of which are important to persons with late stage HIV illness. Primary inclusion criteria included having a DSM-III-R depressive disorder, debilitating low energy, CD4 cell count below 200 cells/mm3, and no history of drug dependence. The trial consisted of open treatment in a 6-week protocol, with indefinite follow-up. Twenty-four men entered the study, 18 of 19 (95%) patients who completed at least 6 weeks of treatment reported substantial improvement with regard to both mood and energy at a median dosage of 10 mg/day. These results suggest that dextroamphetamine is a potentially effective, fast acting antidepressant treatment for this population and call for a larger, controlled trial.

Exercise as a mediator of psychological and nutritional effects of testosterone therapy in HIV+ men.

PURPOSE The purpose of this study was to determine whether exercise mediates the psychological and nutritional effects of testosterone therapy in men with symptomatic HIV illness, low serum testosterone, and clinical symptoms of hypogonadism. METHODS A 12-wk open trial of biweekly intramuscular testosterone injections was conducted, with 54 men completing the trial and exercise assessments. Most (71%) men were diagnosed with AIDS; 41% had a CD4 < 50. One-third of the men were diagnosed with major depression, and nearly half had some evidence of wasting. Twenty-nine men (54%) engaged in exercise (predominantly resistance training) during the trial. Exercisers did not differ from nonexercisers on any measure of psychological well being or nutritional status at baseline. RESULTS After 12 wk of testosterone treatment, those who exercised showed significant improvement in mood (Hamilton Rating Scale for Depression; HAM-D) and overall distress (Brief Symptom Inventory; BSI) (P < 0.000 for both), as well as a significant increase in body cell mass (P < 0.01) and lean body mass (mean increase of 2.6 kg; P < 0.000) as measured by bioelectric impedance analysis. In contrast, nonexercisers showed improvement on the HAM-D (P < 0.000), but not the BSI or measures of nutritional status. CONCLUSION These findings indicate that exercise may be an important adjunct to testosterone therapy in the treatment of psychological distress and wasting symptoms in men with symptomatic HIV illness.

Illness stage, concurrent medications, and other correlates of low testosterone in men with HIV illness.

Our objective was to assess whether illness stage, markers of illness progression, and use of medications believed to lower testosterone are associated with low serum testosterone in HIV+ men. Data were available for 234 HIV+ men screened for eligibility for a study of testosterone replacement therapy and/or an antidepressant trial. A screening interview was used to elicit demographic and medical information. Blood was drawn to measure markers of immunodeficiency and serum testosterone. Thirty-eight percent of the sample had testosterone levels below the normal range. Low testosterone was associated with lower CD4 cell count, later stage of illness, use of megestrol, and older age. Regression analysis showed that only age and use of such medications as megestrol were significant predictors of low testosterone. Given the prevalence of low testosterone in HIV+ men and its link to sexual dysfunction, more research is needed on treatments aimed at correcting or compensating for this hormonal deficiency as well as the study of the impact of such medications as megestrol on testosterone levels in older men.

Testosterone treatment of clinical hypogonadism in patients with HIV/AIDS

The use of testosterone to treat clinical symptoms of hypogonadism and wasting among patients with HIV/AIDS is a relatively new area of inquiry and clinical application. Outcome measures have included changes in mood, libido, energy, weight and muscle mass1-5. The purpose of this review is to identify the questions most commonly raised about risks of testosterone therapy, to review available data which address these questions, and to discuss issues of clinical management. These include treatment indications, measurement issues, and side effects and their management.

Provigil (Modafinil) Plus Cognitive Behavioral Therapy for Methamphetamine Use in HIV+ Gay Men: A Pilot Study

Objectives: To evaluate the efficacy of modafinil combined with cognitive behavioral therapy (CBT) for treatment of methamphetamine (MA) dependence among HIV+ gay men. Methods: In a single blind trial, modafinil was administered for 12 weeks, followed by a 4-week placebo phase. CBT was conducted for 18 sessions over the 16-week study. Primary outcome measures were self-reported use of days per week plus urine toxicology assays. Additional measures included the Beck Depression Inventory, Cravings Scale, and O/C Crystal Use Scale. Response was defined as > 50% decline in days used per week. Thirteen patients were enrolled over an 18-month period. Results: Ten patients (77%) completed the trial, although two discontinued modafinil due to side effects. Six of the ten study completers reduced their MA use by > 50%. Conclusions: These preliminary results suggest good retention using combined medication and psychotherapy, and support further examination of modafinil and CBT in double-blind placebo controlled trials.

Modafinil treatment for fatigue in HIV/AIDS: a randomized placebo-controlled study.

OBJECTIVE To evaluate the efficacy and safety of modafinil in the treatment of fatigue in patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and to assess effect on depressive symptoms. METHOD Patients who were HIV+ and had clinically significant fatigue (according to the Fatigue Severity Scale [FSS]) were included in a 4-week randomized, placebo-controlled, double-blind trial. This was followed by an additional 8 weeks of open-label treatment for modafinil responders and 12 weeks for placebo nonresponders. The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement scale, supplemented by the FSS, Hamilton Depression Rating Scale, and Beck Depression Inventory. Safety was assessed with assays of CD4 cell count and HIV ribonucleic acid (RNA) viral load. Visits were weekly for 4 weeks, then biweekly, with a follow-up visit at 6 months. Maximum trial dose of modafinil was 200 mg/d. Data for this study were collected between December 2004 and December 2008. RESULTS 115 patients were randomly assigned. In intention-to-treat analyses, fatigue response rate to modafinil was 73% and to placebo, 28%. Attrition was 9%. Modafinil did not have an effect on mood alone in the absence of improved energy. At week 4, CD4 cell counts did not change significantly; HIV RNA viral load showed a trend decline for patients taking modafinil but not for those taking placebo. At 6 months, those still taking modafinil had more energy and fewer depressive symptoms than patients who were not taking modafinil, and only those still taking modafinil showed a significant decline from baseline in their HIV RNA viral load. CONCLUSIONS Modafinil appears to be effective and well tolerated in treating fatigue in HIV+ patients. Consideration of its use is warranted considering the high prevalence of fatigue in the HIV community, its minimal side effects, and overall patient acceptance. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00118378.

Treatment of depression in HIV+men: Literature review and report of an ongoing study of testosterone replacement therapy

Our research program was designed to assess androgenic, anabolic, and mood effects of testosterone replacement therapy in human immunodeficiency virus positive (HIV+) men with significant immune suppression and hypogonadism. This article focuses on mood effects. Treatment consisted of biweekly intramuscular injections of testosterone cypionate at doses of 200 to 400 mg. Assessments included psychiatric evaluation using the Structured Clinical Interview for DSM-III-R, Hamilton Rating Scale for Depression, and Brief Symptom Inventory. This is an interim report of 73 men who completed at least eight weeks of treatment. Responders continued for four more weeks and then entered a double-blind placebo controlled discontinuation phase.At study entry, 49% had CD4 counts under 50, and 84% had an acquired immune deficiency syndrome (AIDS)-defining condition. In terms of sexual desire and function, 76% were clear-cut responders at Week 8. Of the 31 study completers who had mood problems at baseline, 26 (84%) were rated as much improved in mood. Mean changes in CD4 cell count and beta 2 microglobulin after treatment were not statistically significant. These findings suggest that testosterone replacement therapy has significant antidepressant effects for men with significant immunodeficiency and clinical manifestations of hypogonadism.